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Hepatitis C virus triggers Golgi fragmentation and autophagy through the immunity-related GTPase M
Marianne D Hansen1,2, Ingvild B Johnsen1, Kim A Stiberg1
1Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, Norwegian University of Science and Technology, 7006 Trondheim, Norway.
Abstract:
Positive-stranded RNA viruses, such as hepatitis C virus (HCV), assemble their viral replication complexes by remodeling host intracellular membranes to a membranous web. The precise composition of these replication complexes and the detailed mechanisms by which they are formed are incompletely understood. Here we show that the human immunity-related GTPase M (IRGM), known to contribute to autophagy, plays a previously unrecognized role in this process. We show that IRGM is localized at the Golgi apparatus and regulates the fragmentation of Golgi membranes in response to HCV infection, leading to colocalization of Golgi vesicles with replicating HCV. Our results show that IRGM controls phosphorylation of GBF1, a guanine nucleotide exchange factor for Arf-GTPases, which normally operates in Golgi membrane dynamics and vesicle coating in resting cells. We also find that HCV triggers IRGM-mediated phosphorylation of the early autophagy initiator ULK1, thereby providing mechanistic insight into the role of IRGM in HCV-mediated autophagy. Collectively, our results identify IRGM as a key Golgi-situated regulator that links intracellular membrane remodeling by autophagy and Golgi fragmentation with viral replication.
Insights
The human immunity-related GTPase M (IRGM) protein regulates Golgi fragmentation during hepatitis C virus (HCV) infection. IRGM links autophagy and Golgi dynamics to viral replication complexes.
Area of Science:
- Virology
- Cell Biology
- Molecular Biology
Background:
- Positive-stranded RNA viruses, like hepatitis C virus (HCV), hijack host cell membranes to form replication complexes.
- The exact composition and formation mechanisms of these viral replication complexes remain unclear.
Purpose of the Study:
- To investigate the role of human immunity-related GTPase M (IRGM) in the formation of viral replication complexes.
- To elucidate the mechanisms by which IRGM influences host cell membranes during HCV infection.
Main Methods:
- Localization studies of IRGM within infected cells.
- Analysis of Golgi membrane dynamics and fragmentation.
- Investigation of IRGM's effect on GBF1 and ULK1 phosphorylation.
- Assessment of colocalization between Golgi vesicles and replicating HCV.
Main Results:
- IRGM localizes to the Golgi apparatus and promotes Golgi membrane fragmentation upon HCV infection.
- IRGM regulates the phosphorylation of GBF1, a key protein in Golgi dynamics.
- HCV infection induces IRGM-mediated phosphorylation of ULK1, an autophagy initiator.
- IRGM facilitates the colocalization of Golgi vesicles with replicating HCV.
Conclusions:
- IRGM is a critical regulator situated at the Golgi apparatus.
- IRGM connects autophagy, Golgi fragmentation, and viral replication processes.
- IRGM plays a previously unrecognized role in HCV replication complex assembly.